Stimulation of a T cell through its T cell receptor (TCR), in conjunction with appropriate costimulatory signals, results in complex cascades of signal transduction events within the T cell that eventually lead to T cell proliferation, differentiation and cytokine production. Although many cellular signaling molecules have been causally related to the various endpoints of T cell activation, the understanding of the detailed intermolecular connections between signaling events is still evolving. The study of various protein kinases is at the forefront of this evolving knowledge.
Multiple families of protein-kinases are present in each cell. The same cell may express several, structurally-related yet genetically distinct, kinases of each family. The activity of the family of serine/threonine protein kinase C (PKC) enzymes has been implicated in T-cell activation. Until the present invention, however, it was unknown which members of the PKC-family regulate the various T cell responses to foreign antigens.
A variety of assays have been used to evaluate the ability of T cells to be activated in vitro and to make predictions about the ability of such T cells to proliferate and/or produce cytokines in vivo. Such methods for measuring T cell activation, however, often involve the use of "immortalized" cells (e.g., hybridomas) or antibodies (as artificial stimulators of the T cell), which may not accurately reflect a normal T cell response in vitro or in vivo. Therefore, there is a need for a system for evaluating antigen-specific T cell activation which can be used as a predictor of and/or regulatory target for T cell activation in vivo.